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Aims: Angiotensin receptor blockers have been shown to reduce heart failure hospitalization and cardiovascular mortality in men and women with heart failure with reduced ejection fraction (HFrEF). It is unknown whether there are differences between men and women in achieved dose and treatment discontinuation due to adverse events of candesartan. Methods and results: We conducted a post hoc analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. A total of 3172 men and 1106 women with HFrEF [left ventricular ejection fraction (LVEF) ≤ 40%] in New York Heart Association class II–IV were randomized to candesartan or placebo. Every 2 weeks, patients were up‐titrated from 4 or 8, to16, to 32 mg once daily, unless a higher dose was contraindicated or not tolerated. Women were older (66 vs. 64 years), had a higher LVEF (29.9% vs. 28.6%), and had more hypertension (54% vs. 47%) than men. The mean achieved dose of candesartan was 21.5 ± 12.6 mg in men and 20.7 ± 12.9 mg in women (P = 0.19). In both the candesartan and placebo groups, cardiovascular death and heart failure hospitalizations were higher in men and women who achieved lower dose levels. Event rates for achieved dose levels of 0, 4 or 8, 16, and 32 mg candesartan were 20.8, 17.2, 14.0, and 10.1 per 100 person‐years in men, respectively, and 23.6, 13.7, 14.0, and 9.1 per 100 person‐years in women, respectively. In each of the achieved dose levels, there was no sex difference in the proportion of patients with an event, neither in the candesartan group nor in the placebo group (P‐value for all > 0.05). There was no significant interaction between sex and treatment‐related discontinuation for hypotension (P = 0.520), an increase in creatinine (P = 0.102), and hyperkalaemia (P = 0.905). Conclusions: In a randomized clinical trial in patients with HFrEF, men and women achieved similar doses of candesartan. Primary event rates and treatment‐related discontinuation due to adverse events were also similar between men and women. [ABSTRACT FROM AUTHOR]

Aims Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into the underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses. Methods and results From a panel of 92 biomarkers from different pathophysiological domains available in 1620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1219, 38% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were up-regulated in patients with AF and HF. In the validation cohort, eight biomarkers were up-regulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, P = 1.33 × 10−12), insulin-like growth factor-binding protein-1 (fold change 1.32, P = 1.08 × 10−8), and insulin-like growth factor-binding protein-7 (fold change 1.33, P = 1.35 × 10−18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort. Conclusion In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies. [ABSTRACT FROM AUTHOR]

Aims  Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with ageing in HFrEF potentially leading to targeted therapies in this vulnerable population. Methods and results  From a panel of 363 cardiovascular biomarkers available in 1611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged >75 vs. <65 years. Second, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly vs. younger patients. After adjustment, multiple test correction [false discovery rate (FDR) 1%], and cross-validation, 27/363 biomarkers were associated with older age, 22 positively and 5 negatively. The biomarkers that were positively associated with older age were associated with tumour cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumourigenesis. Among the 27 biomarkers, WFDC2 (WAP four-disulphide core domain protein 2)—that broadly functions as a protease inhibitor—was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed. Conclusions  In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumour cell regulation were activated, while pathways associated with tumour proliferation functions were down-regulated. These findings may help in a better understanding of the ageing processes in HFrEF and identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Aims: We aimed to characterize ethnic differences in prevalence, clinical correlates, and outcomes of atrial fibrillation (AF) in heart failure (HF) with preserved and reduced ejection fraction (HFpEF and HFrEF) across Asia. Methods and results: Among 5504 patients with HF prospectively recruited across 11 Asian regions using identical protocols in the Asian Sudden Cardiac Death in Heart Failure study (mean age 61 ± 13 years, 27% women, 83% HFrEF), 1383 (25%) had AF defined as a history of AF and/or AF/flutter on baseline electrocardiogram. Clinical correlates of AF were similar across ethnicities and included older age, prior stroke, higher NT‐proBNP, and larger left atria. Diabetes was associated with lower odds of AF in HFrEF [adjusted odds ratio (AOR) 0.79, 95% CI 0.66–0.95] and HFpEF (AOR 0.58, 95% CI 0.39–0.84) regardless of ethnicity. Compared with Chinese ethnicity, Japanese/Koreans had higher odds of AF in HFrEF (AOR 1.76, 95% CI 1.40–2.21), while Indians had lower odds in HFrEF (AOR 0.18, 95% CI 0.13–0.24) and HFpEF (AOR 0.28, 95% CI 0.16–0.49) even after adjusting for clinical covariates. Interaction between ethnicity and region was observed among Indians, with Southeast Asian Indians having higher odds of AF (AOR 3.01, 95% CI 1.60–5.67) compared with South Asian Indians. AF was associated with poorer quality of life and increased risk of 1 year all‐cause mortality or HF hospitalisation (adjusted hazard ratio 1.39, 95% CI 1.18–1.63) regardless of ethnicity. Conclusions: Among patients with HF across Asia, clinical correlates and adverse outcomes associated with AF are similar across ethnicities; however, there are striking ethnic variations in the prevalence of AF that are not accounted for by known risk factors. [ABSTRACT FROM AUTHOR]

Background: Coronary artery disease affects both men and women. In this study, we examine sex-specific differences in occurrence of major adverse cardiovascular events (MACEs) after coronary angiography. Methods: We analyzed data from the coronary angiography cohort Utrecht Coronary Biobank (n = 1283 men, 480 women). Using Kaplan-Meier and multivariable Cox-regression, we tested for sex differences in MACE occurrence. Additionally, we compared mortality with an age- and sex-matched control group from the general Dutch population. Results: During a median follow-up of 2.1 years (interquartile range 1.6-2.8), MACEs occurred in 265 men and 103 women (20.7% vs 21.3%, P = .744). Women with myocardial infarction (MI) had significantly more MACE during follow-up than men (hazard ratio [HR] 1.66 for female sex, 95% confidence interval [CI] 1.10-2.50, P = .015), which was also the case for women who had multivessel disease (HR 1.41, 95% CI 1.03-1.94, P = .031). During follow-up, mortality in women presenting with MI was higher than mortality of women in the general population; men with MI did not show this disadvantage. Conclusion: MACEs occurred more often in women than in men who presented with MI or who had angiographic multivessel disease upon coronary angiography. Clinical trial registration:Clinicaltrials.gov identifier: NCT02304744. URL: https://clinicaltrials.gov/ct2/show/NCT02304744. [ABSTRACT FROM AUTHOR]

Introduction: A genetic basis for atrial fibrillation (AF) is evident in the community, but it remains unclear whether individuals with AF in the context of heart failure (HF) share a similar genetic susceptibility. Hypothesis: There is an association between AF and common genome-wide susceptibility loci for the arrhythmia in patients with HF. Methods: Associations between an AF genetic risk score (GRS) and AF prevalence was studied in the BIOlogy Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF). The GRS was based on twenty-five single nucleotide polymorphisms (SNPs) associated with AF at P-values <1x10-8 in the latest AF genome wide association study. The GRS was calculated by summing the dosage of each AF risk allele (ranging from 0-2) weighted by the natural logarithm of the relative risk for each SNP. Patients were classified into the AF group if they had AF or atrial flutter (AFL) at baseline ECG and/or a prior diagnosis of AF or AFL. The GRS was assessed in the total HF group. Secondary analyses were performed in subgroups based on left ventricular ejection fraction (LVEF); LVEF<40% and LVEF≥50%, respectively HFrEF and HFpEF. Results: A total of 3759 Caucasian individuals from BIOSTAT-CHF with genetic and rhythm data, of which 1783 were in SR and 1976 with (a history of) AF, were identified. The GRS was associated with AF after multivariable adjustment for clinical risk factors; including principal components of ancestry, age, sex, coronary artery disease, hypertension, diabetes and renal disease. The odds ratio for AF was 4.05 per 1-unit change in GRS (95% confidence interval (CI) 2.68-6.13, P=3.7x10-11) in the total BIOSTAT cohort. The GRS ranged from 4.54 per 1-unit change in GRS (95% CI 2.67-7.72, P=2.2x10-8) to 3.43 per 1-unit change in GRS (95% CI 1.08-10.93, P=0.04) in HFrEF (1137 SR, 1125 AF) and HFpEF (223 SR, 307 AF) respectively. Conclusions: The AF genetic risk score was associated with increased AF risk in HF patients, which suggests at least a partially heritable component to the propensity of AF in HF patients. Efforts are warranted to determine the causal mechanisms and extent by which genetic AF susceptibility influences AF risk in patients with HF. [ABSTRACT FROM AUTHOR]